MD-4251: A First-in-Class Oral MDM2 Degrader Inducing Complete Tumor Regression with Single-Dose Administration

  • J Med Chem. 2025 Jul 10;68(13):13249-13267. doi: 10.1021/acs.jmedchem.5c00809.
Ranjan Kumar Acharyya  1 ,  Liyue Huang  1 ,  Angelo Aguilar  1 ,  Biao Hu  1 ,  Longchuan Bai  1 ,  Hoda Metwally  1 ,  Donna McEachern  1 ,  Wei Jiang  1 ,  Yu Wang  1 ,  Qiuxia Li  2 ,  Bo Wen  2 ,  Duxin Sun  2  3 ,  Shaomeng Wang  1  4  5  3
Affiliations
  • 1. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 3. Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 4. Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.
  • 5. Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 40511819 DOI: 10.1021/acs.jmedchem.5c00809
Abstract

MDM2 is a key negative regulator of the tumor suppressor p53 and an attractive target for Cancer therapy. We report the discovery of MD-4251, the first orally efficacious MDM2 Degrader developed using PROTAC technology. MD-4251 induces potent and rapid MDM2 degradation in RS4;11 cells (DC50 = 0.2 nM; Dmax = 96% at 2 h), leading to robust p53 activation. It selectively inhibits the growth of acute leukemia cell lines with wild-type p53, with minimal activity in p53 mutant lines. MD-4251 shows excellent oral bioavailability in mice, favorable metabolic stability, and no CYP or hERG liabilities. A single oral dose induces sustained MDM2 depletion and attains complete tumor regression in vivo. These results support MD-4251 as a promising therapeutic candidate for cancers through depletion of MDM2.

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